Monday, April 13, 2009

A passive approach to influenza

I'm a bit late in the game to this one, since it's been covered in much of the lay press over the past month, but I feel it deserves some further discussion, mostly because of its relevance.

What Jianhua Sui at the Farber here in Boston, with colleagues at the Burnham out in California, and the CDC, (subscription required) have done is potentially develop a new therapy for influenza disease. This has made it around the mainstream press, mostly due to the fears of pandemic illness. Scaling this method up to a pandemic level intervention is another matter entirely, but the science about its utility is outstanding, nonetheless.

Influenza is a notoriously cagey virus, with its two main antigenic determinants, hemagglutinin and neuraminidase, always drifting along, forcing us to reactively change our vaccines every year (that's what the H&N refer to whenever people use words like H5N1, H3N2 and the like). Further, evidence of resistance of our major drugs used to treat the infection is piling up (here and here, for example), making our battle against infuenza a near-Sisyphean struggle, with the especially scary concept of the mutated virus being more fit than the wild-type.

So, what we're left with is trying to completely shift our approach to influenza treatment, focusing on portions of the virus that don't constantly change with the slightest amounts of genetic pressure. That's exactly what Sui's group did: they screened a phage-display library, consisting of about 27 billion unique antibodies, finding a group of antibodies which inhibit, both in vitro and in vivo (mouse model), influenza activity through blocking hemagglutinin activity. These antibodies, on crystallography, bind to a conserved region on the stem region of hemagglutinin, an area which doesn't change so quickly, potentially producing a catch-all group of antibodies effective against every influenza virus. The concept and cost of passively immunizing an entire population to ward off pandemic influenza involves economies of scale that can only be fantasized about at this juncture, but something that deserves further thought after the requisite human studies are performed over the next few years.

One of the lingering questions, that the authors address, is why we haven't figured this out on our own, ie why don't we generate these antibodies after infection, instead of the only transiently useful antibodies that we currently produce? There's no real answer to this, so I'll await further studies before postulating ideas.

It's clear that our current anti-influenza strategies of seasonal vaccinations are only effective in the setting of slowly drifiting virus and significant coverage. In the setting of a significant antigenic shift, further options might be required to avoid pandemic disease, and this option holds definite promise.

Ref: Nature Structural & Molecular Biology 16, 265 - 273 (2009) Published online: 22 February 2009 | doi:10.1038/nsmb.1566

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